2-28412212-A-C

Position:

• chr2-28412212-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005253.4(FOSL2):​c.745A>C​(p.Ile249Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOSL2 NM_005253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35

Genes affected

FOSL2 (HGNC:3798): (FOS like 2, AP-1 transcription factor subunit) The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27579033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOSL2	NM_005253.4	c.745A>C	p.Ile249Leu	missense_variant	4/4	ENST00000264716.9	NP_005244.1
FOSL2	XM_006711976.4	c.796A>C	p.Ile266Leu	missense_variant	4/4		XP_006712039.1
FOSL2	XM_006711977.4	c.679A>C	p.Ile227Leu	missense_variant	4/4		XP_006712040.1
FOSL2	XM_005264231.5	c.*230A>C		3_prime_UTR_variant	5/5		XP_005264288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOSL2	ENST00000264716.9	c.745A>C	p.Ile249Leu	missense_variant	4/4	1	NM_005253.4	ENSP00000264716.4
FOSL2	ENST00000379619.5	c.721A>C	p.Ile241Leu	missense_variant	4/4	1		ENSP00000368939.1
FOSL2	ENST00000436647.1	c.*20A>C		downstream_gene_variant		2		ENSP00000396497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.745A>C (p.I249L) alteration is located in exon 4 (coding exon 4) of the FOSL2 gene. This alteration results from a A to C substitution at nucleotide position 745, causing the isoleucine (I) at amino acid position 249 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.10	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.29	.;B
Vest4		0.37
MutPred		0.30		.;Loss of ubiquitination at K247 (P = 0.0863);
MVP		0.60
MPC		0.36
ClinPred		0.66	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-28635079;